Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002037544 | SCV002115845 | likely pathogenic | Juvenile polyposis syndrome | 2024-11-13 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the SMAD4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1345775). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV004996027 | SCV005503067 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2024-10-30 | criteria provided, single submitter | clinical testing | The c.905-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 7 of the SMAD4 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame skipping of coding exon 7 and is not expected to trigger nonsense-mediated mRNAdecay. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of seventeen amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. |